15 - dehydro - 6,14 - endoetheno and endoethano northebaines and nororipavines



United States Patent 8 Claims ABSTRACT OF THE DISCLOSURE The invention relates to novel derivatives of thebaine and oripavine of the formula:

lieO

and salts of the compounds of the said formula, wherein Y, Q, R and R are hereinafter specified radicals, are prepared by the dehydrogenation of compounds of the formula o N-R I-IeO wherein R and R are each hereinafter specified radicals, and their salts with pharmaceutically acceptable acids are therapeutically useful. The invention also includes pharmaceutical compositions comprising the novel compound or a pharmaceutically acceptable salt thereof, and a carrier, therefor, which may be in unit dosage form.

This invention relates to novel derivatives of thebaine' and oripavine, to their salts, and to processes for their preparation.

. According to the present invention there are provided 3,464,992 Patented Sept. 2, 1969 compounds of the following formula, and salts of compounds of the said formula:

wherein Y is etheno (-CH=CH-) or ethano R is hydrogen, phenyl or tolyl;

R is a methyl group or hydrogen;

R is hydrogen, an alkyl or alkenyl group of up to 3 carbon atoms, a phenyl or a tolyl group;

R is cycloalkyl group of 5 to 7 carbon atoms, an alkyl or alkenyl group of up to 8 carbon atoms, a benzyl or a phenethyl group;

R is an alkyl group of up to 5 carbon atoms, a cycloalkyl methyl group of 4 to 6 carbon atoms, an allyl, methylallyl, dimethylallyl or crotyl group;

R is an alkyl group of up to 5 carbon atoms;

The organic bases of the invention form addition salts with acids. Since the bases of the invention contain the enamine grouping the salts of these bases are iminium salts, for example the perchloric acid salts have the formula:

N R LO 7' 4- C tie O wherein R, R Q and Y have the above meanings and Me is methyl.

It is to be understood that the invention also includes these iminium salts.

The novel bases of the invention may be prepared by the dehydrogenation of compounds of the Formula II;

3 wherein R, R Q and Y are as defined hereinbefore. The compounds of Formula II in which Q is HO R and Y is the etheno group (-CH==CH) are described in British Patents Nos. 902,659, 925,723, 937,214, 969,263, or may be prepared by the methods described in these patents. The compounds of Formula II in which Q represents and Y is the etheno group (CH=CH-) may be prepared by the Diels Alder reaction of thebaine with an acrylic acid ester of the formula CH :CHCOOR The compounds of Formula II in which Y is the ethano group (-CH -CH may be prepared from the corresponding compounds in which Y is the etheno group may also be prearde from the bases of Formula I in which Thus the alcohols may be prepared from the ketones of Formula I in which by reaction with respectively an organo metallic compound for example a Grignard reagent R MgX or an alkyl lithium LiR or with an organo metallic compound for example a Grignard reagent RMgX or R MgX or an alkyl lithium LiR or LiR where X is a halogen atom.

The tertiary alcohols in the special case where R R may be prepared from the esters of Formula I in which by reaction with an organometallic compound such as a Grignard reagent R MgX or an alkyl lithium R Li. The secondary alcohols in which may be prepared from the ketones of Formula 1 m which Q=O=63-R by reduction with, for example, lithium aluminum hydride or aluminum isopropoxide.

The invention is further illustrated by the following examples:

Example 1.7-acetyl-l5-dehydro-6,14-endoethenotetrahydrothebaine (I; R=R :R =Me, Y=-CH:CH)

Mercuric oxide (66 g.) was dissolved in a mixture of acetic acid (96 ml.) and water (1200- ml.) 7-acetyl-6,l4- endoethenotetrahydrothebaine (21.6 g.) was added and the solution boiled under reflux for 20 minutes, during which time mercurous acetate precipitated. The cooled solution was saturated with hydrogen sulphide and the precipitate removed by centrifugation and filtration. The solid precipitated by neutralization of the filtrate with potassium carbonate was collected, washed well with water and crystallized from ethanol when the dehydro-compound was obtained as prisms (11.2 g.), M.P. 104-109 C.

Analysis.-Calcd. for C H NO C, 72.8; H, 6.6. Found: C, 72.7; H, 6.8%.

The perchlorate, prepared by dissolving the base in dilute acetic acid and adding aqueous sodium perchlorate solution, crystallized from methanol as needles, M.P. 189-191" C.

AI'lfllySiS.-Ca1Cd. for C23H25NO4'HCLO4I C, H, 5.5; C1, 7.4. Found: C, 57.8; H, 5.7; Cl, 7.65%.

Example 2.15-dehydro-6,14-endoetheno-7-( l-hydroxy-lmethylethyl tetrahydrothebaine (a) Mercuric oxide (33 g.) was dissolved in a mixture of acetic acid (48 ml.) and water (60 0 ml.) 6,14-endoetherzo-7-( l-hydroxy- 1 -rnethylethyl) tetrahydrothebaine (12 g.) was added and the solution was boiled under reflux for 1 hour. The cooled solution was saturated with hydrogen sulphide and the precipitate removed by centrifugation and filtration. The filtrate was neutralized with potassium carbonate and the precipitate collected and washed well with water. When the precipitate was crystallized from aqueous ethanol, the dehydro-compound was obtained as prisms (7.2 g.), M.P. l53-155 C.

Analysis.--Calcd. for C H NO C, 72.9; H, 7.4. Found: C, 72.7; H, 6.9%.

When the base was dissolved in diluted acetic acid and an aqueous solution of sodium perchlorate was added, the perchlorate precipitated, M.P. 240-242 C. (decomp) Analysis.Calcd. for C H NO -HClO C, 58.1; H, 6.1; Cl, 7.15. Found: C, 57.6; H, 5.9; Cl, 7.5%.

(b) A solution of methyl magnesium iodide in ether (25 ml.) was prepared from magnesium (0.2 g.) and methyl iodide (1.1 ml.), 7-acetyl-15-dehydro-6,l4-endoethenotetrahydrothebaine (0.5 g.) was added and the mixture boiled under reflux for 18 hours. The cooled solution was treated with ammoniacal ammonium chloride solution and extracted with ether to give material M.P. 153- 155, identical in all respects with the dehydrocompound obtained in (a) above.

Example 3.7-carbethoxy-15-dehydro-6,14 endoethenotetrahydrothebaine Mercuric oxide g.) was dissolved in a mixture of acetic acid (220 1111.) and water (780 ml.), 7-carbethoxy- 6,14-endoethenotetrahydrothebaine (50 g.) was added and the mixture boiled under reflux for 45 minutes. The cooled solution was saturated with hydrogen sulphide and the precipitate removed by centrifugation and filtration. The filtrate was basified with potassium carbonate and the solid collected, which after crystallization from ethanol gave the dehydro-compound as prisms (30 g.), M.P. 91-93 C.

Analysis.Calcd. for C H NO C, 70.4: H, 6.7. Found C, 70, O, H, 6.6%.

The following table sets out details of further compounds prepared by the method of Example 2(a). In the column headed Y, A is etheno and B is ethano.

6 Green A.F. and Young RA. (1951), Br. I. Pharmac. Chemother, 6, 572. Male rats weighing 60-80 g. received either saline as controls or one of a logarithmic series of doses of the drug, either subcutaneously or orally 30 and 60 min. respectively before determining pain thresholds. The animals are regarded as showing analgesia if they failed tosqueal on application of a pressure greater than twice the mean pressure required to cause a vocal response in the controls. From the percentage showing analgesia at each does level the EDSO was calculated.

The antitussive activity of certain of the compounds of the present invention was measured in guinea pigs using a modified form of the apparatus described by Winter CA. and Flataker L. (1954). I. Pharmac. exp. Then, 112,

Reflux M.P. Percent found Percent calcd.

Ex. R R R R Y (hours) percent C. C H Formula C H 4 Me Me Me Et A 0.5 40 170-171 72.9 7.6 C24HaiNO4 72.9 7.4

5 Me Me Et Me A 1.0 60 72-75 73.7 7.9 CH31NO4 73.3 7.6

6 Me Me Et CH I A 0.25 40 123-124 73.6 7.8 C2sHa7NO4 74.4 8.2

7 Me Me n-Pr Me A 1.0 55 192-194 73.6 8.0 O26H33N04 73.7 7.9

8 Me Me n-Bu Me A 2.5 70 168-170 74.4 8.1 C27H85NO4 74.1 8.1

9 Me Me n-Am Me A 1.15 50 99-102 74.5 8.3 C2s a7NO4 74.5 8.3

10 Me Me O Me A 0.5 60 182-185 73.7 8.0 C29H3sNO4 74.8 8.4

11 Me Me O Me B 1.5 70 164-165 74.5 8.8 C29H41N04 74.5 8.8

12 Me Me CHzPh Me A 1.0 65 195-199 76.3 7.2 CH33N04 76.4 7.1

13 Me Me C'HzCHzPh Me A 1.25 50 159-160 76.1 7.3 C31H35N04 76.7 7.3

14 H Me O Me A 0.5 142-145 72.1 8.0 C28Ha5NO4HzO 71.9 8.0

15 Me Me Me Me B 1.5 117-118 72.5 7.7 C24Ha1N04 72.5 7.9

16 H Me Me GH -Q A 0.75 239-240 73.9 7.4 C2aHaiNO4 74.1 v 7.4

17 Me Me Me CH B 1.25 65 136-137 74.2 8.0 C27Ha5NO4 74.1 8.0

18 H Me n-Pr CHzCH=CH2 A 0. 75 40 236-238 73.4 7.7 C27HsaNO4. 73.3 7.9

In the above table represents eyclohexyl.

The following are further examples of compounds in accordance with the invention which may be prepared by the methods detailed above:

The novel bases of the invention in which Q is and their salts with pharmaceutically acceptable acids, are useful and valuable as analgesia. In addition to this analgesic activity certain of the compounds also possess antitussive activity.

A test procedure which indicates an analgesic action similar to that of morphine is the tail-pressure method of Groups of 12-36 guinea pigs were exposed for 5 min. to a 20% citric acid aerosol. Drugs, or saline for control purposes, were given either subcutaneously or orally 30 and 60 min respectively before recording the coughs occurring in each group. The reduction in number of coughs at each does level was assessed by comparison with the controls and plotted against the logarithm of the dose given. The dose required to inhibit the number of coughs by 50% was determined.

The analgesic and anti-tussive activities of a number of the compounds which are described in the Examples are set out in the tables. For comparison the results of corresponding tests using codeine and morphine are given.

Analgesic, Antitussive, EDsumgjkg. EDaumgJkg.

Example No.2

The compounds were administered orally (PO), subcutaneously (SC) or intraperitoneally (IP).

Additionally, supplementary routine tests known to those skilled in the art may 'be carried out to assess the importance of side actions frequently associated with morphine-like analgesics. These include such actions as onset and duration of action, development of tolerance, respiratory depression, addiction liability, relative effects by oral and parenteral administration, and inhibitory effects on the gastro-intestinal system.

When mixed with suitable excipients or diluents, the compounds of this invention can be prepared as pills, capsules, tablets, powders, solutions, suspensions and the like for unit dosage, and to simplify administration. As analgesics they will relieve pain by direct action on the nerve centres or by diminishing the conductivity of the sensory nerve fibers. As antitussives they depress the cough centre in the brain.

The enamine grouping is a reactive function, and by virtue of this reactivity the novel IS-dehydrothebaine and oripavine compounds of the present invention are also useful as intermediates in the preparation of 16-alkyl derivatives of thebaine and oripavine as is set out in greater detail in our co-pending application No. 715,498 filed concurrently. These compounds, as their iminium salts, may be reacted with organo metallic compounds e.g. Grignard reagents or alkyl lithiums with the production of l6-alkyl thebaine and oripavine compounds. These latter compounds are therapeutically useful because of their power to affect the nervous system, particularly because of their central effects such as analgesic action. Thus, the iminium salts of formula may be reacted with organo metallic compounds for example a Grignard reagent, R MgX or an organo lithium compound R Li to give 16-alkyl derivatives of thebaine and oripavine of the formula wherein R is a phenyl or tolyl group, a cycloalkyl group of 5 to 7 carbon atoms, an alkyl or alkenyl group of up to 5 carbon atoms, a propargyl group, a benzyl or a phencthyl group.

8 We claim: 1. A compound of the formula:

MeO

Q wherein Y is etheno (CH=CH-) or ethano or a pharmaceutically acceptable salt thereof.

3. A compound of the formula:

R is methyl or hydrogen;

R is hydrogen, phenyl or tolyl;

R is hydrogen, alkyl or alkenyl or up to 3 carbon atoms, phenyl or tolyl;

R is cycloalkyl of 5 to 7 carbon atoms, alkyl or alkenyl of up to 8 carbon atoms, benzyl or phenethyl;

R is allyl, methylallyl, dimethylallyl or crotyl; and

R is alkyl or up to 5 carbon atoms, or a pharmaceutically acceptable salt thereof.

9 10 4. 15-dehydro-6,14-end0etheno-7-(l-hydroxy l-rneth- OTHER REFERENCES ylpentyl)tetrahydrothebaine. B {1 5. 15-dehydro-6,14 endoetheno 7 (l-hydroxy-l- 2 3 Jour' Chem methylhexyl tetrahydrothebaine.

6. 15-dehydro-6,14-endoetheno 7 1 hydroxy-l- Bentley Chem 5 3273-80 (1967). cyclohexylethyl)tetrahydrothebalne. B 7 a1 J A Ch S 7. 15-dehydro-6,14-endoethano 7-(1-hydroxy-1-cycloi- H em, 00., hexylethyl tetrahydrotheb aine. 3 2'8 1-9 2 1967) s. 15-dehydro-6,14-endoethen0-7 (l-hydroxy-l-benz- Bentley Jour- Chemylethyl)tetrahydrothebaine. 10 3293-?3303 (1967).

Bentley et. al.: Jour. Am. Chem. Soc., References Cited 3303 11 (1967). UNITED STATES A S Bentley et. aL: Jour. Am. Chem. 500., 3,240,782 3/1966 Brossi et a1. 260286 15 331241 (1967) 3,285,914 11/1966 Gordon 260-285 I 3,329,682 7/1967 Bentley 260 285 DONALD DAUS, Pflmal'y Examlfler FOREIGN PATENTS 6,700,612 7/1967 Netherlands.

US. Cl. X.R. 

